We propose to use biochemical, behavioral and electrophysiological procedures to expand on a series of findings with unique relevance both for understanding the mode of action of pharmacological and non-pharmacological antidepressant therapies and improving the treatment of depression. The findings referred to are the following: 1) Repeated treatment with tricyclics, electroconvulsive shock and a monoamine oxidase inhibitor as well as "atypical" antidepressants such as iprindole all clearly induce a progressive subsensitivity of substantia nigra dopamine (DA) autoreceptors as measured by single-unit electrophysiological techniques and microiontophoresis (autoreceptors are DA receptors located on DA neurons). 2) DA autoreceptor subsensitivity is a time-dependent phenomenon. When triggered by acute or short-term antidepression treatments, it undergoes progressive enhancement with the passage of time, regardless of whether treatment is again administered. This finding may explain the enigma if the therapeutic delay in depression. It also raises the important possibility that the critical neuronal changes which eventually lead to therapeutic efficacy may be triggered equally well by short-term treatment as by daily drug administration. 3) Repeated administration of tricyclic antidepressants frequently changes the response of DA neurons to autoreceptor stimulation from one of inhibition to excitation. We will follow up on these results by determining the extent to which they generalize to other antidepressant treatments and are specific to such treatments and whether they are peculiar to DA neurons or demonstrable in other neurochemical systems.